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Credit: UC Santa Barbara Neuroscience Research Institute
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Interview of Paul Hansma by David Zierler on May 25, 2020,Niels Bohr Library & Archives, American Institute of Physics,College Park, MD USA,www.aip.org/history-programs/niels-bohr-library/oral-histories/45465
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In this interview, Paul Hansma, research professor in the department of physics at the University of California, Santa Barbara describes his childhood growing up in multiple places due to his father’s academic work at numerous colleges and his early interests as a tinkerer. Hansma recounts his experience at New College and the unique curriculum offered there, and he discusses his graduate work at Berkeley, where he worked with John Clarke and where he conducted research on electron tunneling. He explains the circumstances leading to his appointment of UC Santa Barbara where he initiated electron tunneling spectroscopy, and built pioneering microscropes. Hansma discusses his work on the atomic structure of bones and studying bone deterioration. At the end of the interview, Hansma discusses his research work in the neuroscience of chronic pain.
Okay, this is David Zierler, oral historian for the American Institute of Physics. It is May 25, 2020. It’s my great pleasure to be here with Professor Paul Hansma. Paul, thank you so much for being with me today.
Okay. So to start, please tell me your title and institutional affiliation.
I’m a research professor at the University of California Santa Barbara. I’m in the physics department, and I have an appointment in the Neuroscience Institute.
Okay, great. Now let’s go back to the beginning. Tell me about your family background and your early childhood.
Well, my father was a professor of health education. My mother was a housewife, very interested in the church. So I grew up a lot of different places because my father kept losing his job or not getting tenure. So his first job was in Greeley, Colorado and then Denver, Colorado and then Englewood, Colorado and then Tucson, Arizona and then Scottsdale, Arizona. Then I went off to undergraduate at New College in Florida, and then I went to grad school at UC Berkeley. After that, I came directly to UC Santa Barbara as an assistant professor.
Now Hansma is a unique name. What’s the national origin of it?
It’s Dutch, and it comes from the Friesland region of the Netherlands where they have a lot of horses.
It’s kind of rough. It’s kind of viewed as kind of a low-class region where the farmers are.
Okay. Where were your parents born?
They were both born in Michigan.
Is that where they met also, in Michigan?
No, they met in Denver, Colorado.
Okay, all right. So where would you say you spent your formative years growing up? What was the largest stint you had growing up…the longest stint, I should say?
From what ages?
Fifth grade until the middle of my senior year.
Oh, okay. Okay. I’m curious. When did you start to develop and exhibit an aptitude in math and science?
It was during that time. My father was a professor health education and he was an athlete himself, a good cross-country runner. So I tried out a lot of different athletics … baseball and then I was on the basketball team in junior high. I actually won a letter and I had a letter jacket. Then in high school I went out for football and then track and then cross country. I was never very good at any of those sports. Cross country I could do better than any of the rest of them because it didn't really require any skill. It just required when you felt so bad running that you had to go to the side of the trail and vomit and then you were willing to go off and run some more and you felt better while you were vomiting than when you were running. That’s all that cross country took, just guts, and so I could do that. But luckily, my feet gave out. I went to the doctor and he said I should quit and I did.
So then I started volunteer work with a chemistry professor mixing up solutions, and the year after that I worked with the physics professor setting up demos. Meanwhile, at home I always liked to build things. I, for instance, was building an amateur air liquefier in high school. My mother would drive me to junkyards and pick up an old compressor for that and coils and all this kind of stuff. They were very supportive of me building things. I built a lath house to grow orchids in. I built a lot of stuff, cloud chambers, Van de Graaff generator. I had a big Van de Graaff generator that I built that had a terminal about this big around, and it would shoot sparks like this. I would shoot them from there to my head and to my arm. It would make little welts kind of on there. At any rate, that was a fun Van de Graaff generator. So I liked to build things. I built a still with a fractionation column made from an old bicycle pump body and stainless steel scrubbers to distill lilac vegetal and get drinking alcohol. I took it to college in a mouthwash bottle with a little blue food coloring and a little mouthwash for fragrance.
I just always liked to build things.
Now did your father involve you in his academic interests? Did he share with you sort of his scholarship or his process when you were growing up?
He was a health educator, and so he was very interested in health and healthy living and exercise and diet and all that sort of thing. He certainly transmitted all of that. He was not really very successful as an academic, so in a way he just served as an example to me. I thought I would never do that because I saw all the trouble he had and losing his job over tenure and the whole family and, you know, problems. So I thought I would never do that. But at the same time, when I was in graduate school, then I talked to someone who had just come from industry, and he was talking about all the problems of working as a scientist in industry, which was basically that you don't call the shots about what you want to do.
You know, you're told what you have to do. He had worked at RCA Labs. That got acquired by the same parent company that had Banquet Foods, and they felt that a good project for RCA Labs would be to discover how to get more meat off of chicken necks. He was deeply offended. Now to me, that sounds like kind of an interesting problem, but he was deeply offended, this world expert in semiconductors and now he’s asked to get more meat off of chicken necks. So he quit.
But at the same time then, I thought, well, I’ll give academics a try. I did interview some places, and I got a job right out of college because the University of California at Santa Barbara was just starting up and they realized that they couldn't compete with the better schools for the best candidates. So they came up with the idea-- Vince Jaccarino and Doug Scalapino came up with the idea of why don't we try to hire someone directly out of PhD, where the other institutions like Harvard and Princeton and so on, aren’t looking. They’re all looking for post-docs. They’re all looking for people with post-doctoral experience who apply for their jobs. So why don't we see if we can grab someone directly out of PhD? So I was hired on that basis, and I ended up getting tenure four years later. So I had tenure by the time I was 30. I got tenure just about the same time my father did.
I had kind of learned from him that you really had to bust your butt to get tenure, that this was a major, major thing.
And I worked probably 60 hours a week from the time I entered graduate school until I got tenure, just knowing that that’s what it took.
Right. So let’s back the narrative up a little bit back to high school. When you were thinking about college, were you thinking specifically about physics programs that you wanted to work in, or did you have sort of more general interests at that point?
Well, physics because I had read an insurance company pamphlet that was talking about “So you want to be a physicist,” and I also read their pamphlet for some other occupations. But this one was talking about how what with atomic energy coming in, there was so much demand for physicists that if you were a physicist, it was really easy to get a job. And I knew getting jobs was hard from my father’s experience. So the idea that I liked building things, I was good at physics, and that this supposed guaranteed employment was very appealing to me.
Now ironically, as it happened a lot of people had that same feeling, and the year I graduated, 1972, was the worst year ever. I don't know; it may have been exceeded by now. But last I checked, it was the worst year ever for the ratio of physics jobs to physics graduates.
[Chuckling] So it’s kind of ironic that I went into it because there would be so many jobs, but in fact there were very few. But luckily I got one of the ones that were available.
Now I’m not familiar with this literature that you cited, “So you want to be a physicist.” Do you remember what the company was or how you came into contact with it?
It was some insurance company. It was a little pamphlet. It was a little pamphlet, maybe this size, two or three pages folded over, and…yeah.
And you came across this as a high school student.
Now what kinds of schools did you apply to? Did you mostly apply to small schools for undergraduate?
Well, I applied to New College, which was just starting out. It was their first year and they were going to have 100 students only. They had Arnold Toynbee and they had some other famous people and this was going to be a new experiment in education. It was patterned after New College, Oxford and it was going to be a very, very high-class college with small class sizes, all that kind of stuff, in Sarasota, Florida. So they sent to all the National Merit Finalists their “Please apply here” kind of things and I did. I forget where else I applied. I think I applied to MIT and some other place. I forget where I applied. But the thing was with New College, they gave me 100% scholarship that covered room, board, tuition, everything, so it was a free ride. You know, my parents were never wealthy, and the money they did have they always wanted to give to charity. So the idea that they wouldn't have to support me in college was very attractive.
Sure. I wonder if New College, their overall aim was to attract students who might otherwise go to Ivy League colleges and universities at that caliber.
Looking back, I assume at some point you thought that it perhaps was a bit of a risk to go to a brand new school that didn't have the name recognition of obviously some other schools that you might have considered. Did that risk pay off, would you say?
Yeah, it worked out fine. I mean, it got really dicey because at the end of the first year, all the faculty but two quit. What happened was they had a president and the president of the college, he was primarily a fundraiser. He had identified Sarasota, Florida as a great place to start a college just based on demographics, that there was a lot of wealth in the community, and there was no college there. Wealthy people like colleges because of plays and all the cultural activities that having a college offers, and so he figured this would be a primo location to have a college. His vision of it was that we would wear academic robes like in New College, Oxford. His fantasy was that he would bring in donors and they would see all these students in academic robes and be very happy with what they were funding this novel and wonderful thing. They’d go to the lectures by Toynbee and Margaret Mead and others in the college center. There would be this little center of high culture for people to get behind and support. But as it happened, these are students in Florida. When the donors visited they did not see academic robes. They saw the students wearing casual attire and swimming suits.
It was in the pink marble mansion of Charles Ringling, John Ringling’s brother, right next to the Circus Hall of Fame and John Ringling’s mansion. So the donors who came in see the students sprawling in shorts and swimming suits and so on all in this pink marble mansion and were basically horrified. So he was trying to get the students to conform to his hopes and the dean was more concerned with academics. The dean was very interested in building up academic programs and so on, and the president was more interested in raising money. The two of them were at odds, so the dean quit. Well, the dean had recruited most of the faculty, so when the dean quit, all the faculty but two quit.
Meanwhile, also it was patterned after England in the sense that nothing counted. It was a three-year school, 11-month years, three years, and nothing counted during the first year. There were just going to be two weeks of comprehensive examinations at the end of the first year. Now the problem was that a lot of these students who came, they were used to being very bright. They were used to being able to do well in classes without that much studying, and here they are. They’re in Sarasota, Florida.
At first we were living in this luxury hotel because the hurricane had blown out the foundations of the dorms which had been designed by I. M. Pei. We later learned that the dorms were designed by I. M. Pei and this whole thing was done like it was so it could be a conference center if the college folded. [Laughs] So one of the trustees owned this resort hotel and we were living in this resort hotel. I mean I was on the 16th floor, I think it was, of this resort hotel, corner room, beautiful view, Gulf of Mexico. It was fabulous.
But then winter came (tourist season). The dorms still weren't ready, so some of us were lucky enough to live with faculty members. I lived with Dr. French, who was a wonderful statistician. I was able to live with him and his wife, and some other students were lucky enough to live with faculty. But the others -- the boys were living in what had been Charles Ringling’s horse stables, and the girls were living in the science lab. They had cots in the science lab. And now comprehensive examinations are coming and a lot of these students hadn't studied at all. They were panicking. So at the end of the first year you had all these panicking students that are living in these marginal characteristics, all the faculty but two leaving, and so things looked a little dicey at that time.
This is amazing. Did you ever think about leaving?
I thought about it, but then I said, “You know, I can get a good education here. There are bright people to teach me, and there’s always the library if they can't recruit another faculty. There’s always the library and it’s a free ride.” I mean, all my expenses are paid. So I stayed, and it worked out just fine. Some people were concerned. There were never any grades at New College, but some people were concerned that this would make it very hard to get into graduate school because not only was it an unknown, unaccredited college, but also there were no grades. But as it turned out, Berkeley was quite happy to depend on GRE results and, of course, they got thoughtful recommendations because the professors actually knew us. So they got good recommendations and GRE scores, and that was sufficient for them to admit us. So I think that those of us who were serious students did fine in going to grad schools.
Now what was the physics department like? Was there a separate physics department, or was it more an overall science program?
It was a science department and there was one physics teacher. The first year was general liberal arts education. Then they brought in a temporary physics teacher from UCSF for the second year, and then they got a permanent one for the third year.
When you were applying for graduate schools, what kinds of schools did you apply to? I should also ask to what degree was your identity as a physicist pretty well formed by the end of your undergraduate education? In other words, did you have an idea if you wanted to do sort of more applied physics or more theoretical physics?
Let me try to think. [Pauses] Well, I think I was always more interested doing something that was going to help people. My parents were very, very into that and devoted their lives to that. So I was interested in doing something with a potential to help people. I was very good at mathematics. There’s a general GRE and then there’s subject GREs. I took the one in physics and in math, and in physics I got 99th percentile; in math I got 99-plus percentile. So I was always able to do math pretty easy.
When I went to Berkeley, they had this advancement to candidacy exam that you were expected to pass before you could go on. Normally you would pass it at the end of your first year if you were lucky, and if you didn't pass it at the end of the first year you were given another chance to pass it later on. But they also decided, “Well, let’s just give it to all the students when they come in to decide what classes to put them in so on.” I passed it on entrance. So New College gave me a good education, and yeah… I don't think I’m answering your question, though. What was your question?
Well, the question was, I mean, given that it was such a tiny program, right, that perhaps at a larger school you might have had a broader exposure to all of the subfields in physics, and that might have sharpened or at least broadened your view in terms of the kinds of physics that you would want to pursue as a graduate student. I mean, in other words I’m specifically thinking of had you known specifically that you wanted to pursue theory or applications or experimentation, that it would not have just influenced the kinds of programs you applied to, but perhaps even specific professors that you wanted to work under.
Yes, and certainly that’s my hope for the undergraduate students who work in my lab at here at UC Santa Barbara. The idea is always yeah, give them lab experience. Let them see what they like to do, what they don't like to do. Do you like to build things with your hands? Do you like to solder? Or do you like to work at computers? So certainly in principle that would have been beneficial to have a taste of research, and certainly that’s a justification for the University of California being the way it is, right? I mean, we teach one-third as many courses as we would if we were in a strictly teaching school, and the main justification for it is that we’re educating students to do research, both graduate students and undergraduates. So yeah, in principle that would have been very useful.
In practice, I built apparatus there at New College. I built a linear accelerator. I built a vacuum system for them and some other stuff for instruction and I had fun building stuff because they had nobody else to do it. They could use some of it—not the linear accelerator, which never worked very well, but they could use some of the other stuff such as a vacuum system for their undergraduate labs and that kind of thing.
I mean I’m curious, Paul, if one of the attractions to Berkeley was, given the size of the program and given how nationally recognized it was in almost every area of physics, if it made sense for you to go there just because you weren't limiting yourself from the beginning.
That may have been a consideration. I think the primary consideration was that it’s very hard to get tenure. It’s very important to work hard and come from a good place, and if I came from Berkeley, I’d have a better chance at getting a good job. I’d have a better chance of getting tenure, and so I felt that Berkeley was a place where I could get a good physics education that would help me get tenure.
Now before we move on to the sort of academic side of things at Berkeley, you're coming there in the late 1960s, and so I’m curious in terms of what’s going on culturally and politically—first, how that influenced your ability to do your own work and how involved you were in those events—you know, not as a student, but as a concerned young citizen.
[Laughs] Yeah. I was never concerned in that way, except for not wanting to be in the draft myself personally. But I never participated in any of the demonstrations or anything like that because I was too focused on my classes and then research. I would see them. I’d walk around them sometimes on my way to the lab, and then I’d learn about them on the evening news that night. And I got trapped once in the gym after playing handball and there was tear gas everywhere. I got locked in the gym and had some incidents like that, but basically I never participated in that. The only effect of all of that was that it totally engrossed my graduate advisor, who got totally taken over by it and lost interest in physics or supervising grad students, and then he was denied tenure. He was brand new and he got denied tenure, understandably. Later, he became a tenured professor of political science at Berkeley.
Yeah! [Laughing] But yeah, that was the main way it affected me. It gave me an advisor who was more interested in revolutionary politics than in advising me.
[Laughs] Okay. Well, I’m curious. Given your very unique interests and the way that you’ve developed your career, at what point-- Was it in graduate school that you started to think about applying your expertise in physics to human health issues or did that come later?
Later, I would say. It came… Well, no. Actually, I shouldn’t say that. Even in graduate school… No, even in graduate school because I was working on thin film electron tunneling junctions, and the guy in the next lab, John Clarke, who, bless his heart, really served as my main graduate advisor since my advisor wasn’t interested, you know, in science. [Chuckles] But John Clarke was a really good scientist and he was kind enough to help me out, as well as Paul Richards, on the other side. So these two guys served as my graduate advisors, despite getting no credit for it or anything.
John was interested in superconducting magnetometers, which are now the heart of magnetoencephalogram, for example. At any rate, these were the early days. He was making some with globs of solder on wire, and it was clear, I think, that what was needed was thin film junctions that could be reproducible and you could make a lot of them and so on and so forth. But thin film junctions had a problem, which is they had too much hysteresis. Well, I figured out a way to eliminate that and make them suitable for use in magnetometers and published a paper on that. Those are used to this day. He adopted them and then he became one of the real leaders in developing the technology of magnetoencephalogram. Ironically, I’m just collaborating now with a group at Berkeley who works in magnetoencephalogram. [Laughs] So that was a health-related thing from very early on.
Yeah, I would say I was always interested in health applications because my father—you know, he was a professor of health education and my folks were very committed to what can you do to help people? So that seemed like a good way to do that.
Now in terms of your curriculum, what was the rough breakdown between coursework and lab work during your first years at Berkeley?
The first year was mostly coursework. The second year was sort of 50/50 and after that it was all research.
Mm-hmm [yes], mm-hmm [yes]. What was your process? How did you go about developing your dissertation topic?
Kind of muddling along, I would say. Since that time, I’ve never really been a fan of dissertation topics. None of my students have really had a dissertation topic in the sense of, you know, “This is your dissertation topic, and now you’ll work on this dissertation topic until you finish a dissertation.” My view is that dissertations are archive documents that are of little or no interest to the scientific community. They just get put into long-term storage in libraries and nobody ever looks at them. I maybe have looked at one or two dissertations in my whole scientific career, and then I’ve only looked at them because the people hadn't published the underlying research.
So my feeling was always what was important was papers, papers that got out there, and so basically a dissertation in my lab is just papers stapled together. You're then try to invent some link between them. Generally you can find some link between what you’ve done, and that’s been the challenge for my graduate students, you know. Basically we focus on papers. We focus on what’s the next thing to do? What’s the next best thing to do, and then when it’s time to graduate, staple them together with some kind of connective narrative.
Right. So if I could pigeonhole you just a little bit in terms of learning about what your dissertation was, what was that connective narrative as you saw it?
What did you feel like your contributions to the field were?
Well, my main contribution was, I think, the shunted Josephson junctions, which then kind of became widely adopted. I figured out a practical way to vacuum deposit resistive shunts close enough to the junctions, for example very thin circles of metals under or over crossed film junctions. And I demonstrated how you could eliminate hysteresis by careful choice of the metal resistance compared to the peak Josephson current. It’s not that I ever really even got credit for that because mostly the people just started using them, and that was fine. But at any rate, I would say that would be my main contribution.
Mm-hmm [yes], mm-hmm [yes]. So you were saying earlier that you got the job at Santa Barbara straight out of graduate school. No post-doc. Now obviously, part of the value of a post-doc is to gain further expertise before going into that traditional tenure-line position, so I’m curious. As you were weighing the options, obviously with the ultimate goal being to gain tenure, did you feel like that was a calculated risk? Or in being offered the tenure-line position straight out of the box, that that was definitely the safer route to go?
I don't remember.
You were probably just happy to get the job offer.
I was, because the thing was the job offer came from this Doug Scalapino. I had worked with him and John Clarke. They had a contract from the Navy to investigate the use of superconducting magnetometers for detecting submarines, something nobody wanted to succeed. [Laughs] It’s ironic because they wanted it to fail because if you could detect submarines with a magnetometer from a plane, that’s the end of this stalemate we had with the Soviet Union and do to this day -- everybody can destroy everybody else because your submarines are hidden. So nobody wanted to be able to find them, but if it were possible to find them, the US wanted to know that, right? [Laughs]
So at any rate, they wrote this paper, and I had done work on superconducting magnetometers, the theory of it and stuff, for a class I took also. I got an A+ on this paper where I had unified a couple of approaches that were out there, one by Feynman and another one, and shown how they were at opposite ends of one model. So anyway, they hired me to edit this report they were making. I did that and in that way I met Doug Scalapino, who was at UC Santa Barbara, and he was the one with Vince Jaccarino who had the idea, “Let’s hire someone right out of grad school.” So they knew of me because of my work on their report.
I found Santa Barbara very attractive because I regarded Doug Scalapino as a super good physicist, and there was nobody here in his field of low temperature physics to do experiments. I thought, wow, this is great. I can go there and I could be the experimentalist to his theory and so on. Plus, it’s Santa Barbara—I mean it is an amazingly wonderful campus. It’s just beautiful. It’s right on the ocean. It’s the only UC campus that’s on the ocean. It’s fantastic, and I thought if you’ve got someone like Doug Scalapino there and this location, this is going to grow and be a good thing.
It’s going to be a good department to join, and that turned out to be true.
Now I’ve interviewed many of your colleagues, including Doug, who are a little senior to you who came to Santa Barbara maybe a decade or five to seven years earlier, and I’ll pose to you the same question I did to them. How much do you feel like the physics department was in growth mode by the time you got there? Was it already well-established because of that earlier spurt of hires in the mid-1960s, or do you feel like it was still very much in growth mode in establishing its name?
It was still very much in growth mode and establishing its name. But it had some great people. Especially important for me were Doug Scalapino and Herb Broida. I kind of had a dearth of advisors, you might notice. As an undergraduate, I didn't work in anybody’s research lab because nobody had a research lab. As a graduate student, my advisor was interested in radical politics. I didn't have a post-doc. So I had had much less advising than the average beginning assistant professor. In that respect, I’m very, very grateful to Herb Broida. He was in the next office to me, and he really served as a mentor for me. He taught me a lot of things, the most important of which was to do every experiment as poorly as possible.
[Laughs] What is the basis for that advice?
The basis for that advice is that if you try to design the perfect experiment, you’ll never be able to do it, especially if you're getting into some kind of new field, making some kind of new measurement. You’ll never be able to anticipate all the problems that you're going to run into and you may imagine some things are problems that turn out to be trivial. So the idea is do it as poorly as possible. Do something using what you already have including Scotch tape and rubber bands. Do the measurement in some way and then improve it and iterate.
So I always iterate my scientific apparatus. I’ll build the first thing, just build something, you know, and then see how it works and learn from how it works and then build the next one and the next one and the next one and the next one. I’m currently on prototype number 8 of the pain meters, for example. I built 40 atomic force microscopes. I built 26 bone-testing instruments and always in this iterative series of, you know, build it quickly as you can and then see how it works; get feedback.
So it sounds like the approach is to embrace the problems from the beginning because discovering the problems is as fruitful as discovering whatever solutions you were looking for in the first place.
Yes. I gave a talk about “poorly as possible” in response to an invitation from graduate students at Harvard who had a seminar series with funding to invite. I gave it a few other places after that. One place was in the Netherlands and afterwards this student came up to me and he said, “Boy, I wish I had heard your talk two years ago. My advisor gave me the job of measuring the light output from this phenomenon that they had been studying in the lab and they thought might be emitting some light. So I looked about how to detect light and I wanted to be sure I could detect the light. So I built a photon-counting system to be sure it could detect a very small amount of light, even if the light was very small.” He had this elaborate dewar and he said he spent… I forget the amount of money he said. I think he said $15,000 and a year and a half building this apparatus, and when he did the first test, there was so much light that his quantum detector didn't even work because it was overloaded! He ended up having to put neutral density filters in front of the sensitive detector. He had to decrease its sensitivity for it to even record. He said, “If on that first day when he gave me the project, if I had just taken an elementary photodetector, a tiny little photodetector, and put it down in the dewar, I would have seen that there was plenty of light. I didn't have to build a low-light system or anything like that.”
Now from the beginning did you stay involved with electron tunneling spectroscopy? Did you continue on with that research?
Yeah. I actually initiated electron tunneling spectroscopy at Santa Barbara. I had been doing other electron tunneling at Berkeley, like superconducting electron tunneling, and then when I got to Santa Barbara, I learned about inelastic electron tunneling spectroscopy and that sounded cool and something to do. Then I had this friend named Bob Coleman and he came and visited. While he was there, we invented a liquid doping technique for doing this which made it possible to study a much wider range of molecules. So the field briefly took off, and that’s the basis on which I got tenure.
Doug Scalapino had done the theory on inelastic tunneling spectroscopy. He went to a conference that a newcomer to the field had set up, and at this conference, basically everybody was talking about my work. It became clear to him that I was the leader of the field, and I think on that basis, plus a job offer from University of Pennsylvania, is why I got tenure so early. So that was nice.
But then I started to realize that, man, this is not going to help anybody. Inelastic electron tunneling spectroscopy is just too obscure, having to use liquid helium and dewars and put your molecules in this geometry. I realized it was of some academic interest, but it was never going to help anybody relieve their suffering. This was a dead end as far as I was concerned.
So then I started exploring its application to surface science to try to salvage it, and it looked like maybe it would be helpful there. Surface science was hot at that moment with the mantra --Everything happens at surfaces, and so let’s study surfaces. So I thought, well, I could get into surface science.
So I went to UC Berkeley on a sabbatical and worked with Gabor Somorjai. He had 16 ultrahigh vacuum chambers and I worked with one of his grad students. But I discovered surface science was really not for me. We had this crystal that was about a centimeter in diameter, and it was behind a window, a few centimeters behind a glass window. You could look at it. We had cleaned it and we’d spent two weeks baking out the system. Then you’d heat the crystal and you’d sputter it and heat it to anneal it over and over again. So after a couple of weeks, the sample was ready for experiments.
The student I was working with went to a conference and I was left with the apparatus. As I was doing it, it had two leads onto that crystal to heat it. I turned up the power and one of the leads popped off. I could just see it right there inside just a few centimeters away, and I realized it was going to be over two weeks until I’d be looking at that same crystal in its same condition with the lead reattached. I thought, man, this is not as poorly as possible. This is a nightmare.
Then what happened—it was really fortunate—is I had Gabor Somorjai over to my apartment and I asked him, you know, did he think I should get into surface science like he was and he said no. I said, “Why not?” He said, “You're an inventive guy. Surface science as it exists now is primarily at the vacuum-solid interface. We create this clean crystal in ultrahigh vacuum and we put all the molecules on it and all this kind of stuff. You know, that’s basically irrelevant to the real world. There’s no catalysis that happens like that. We’re kind of hoping it will have application to catalysis, lubrication, corrosion, all that kind of thing, but really, most everything happens at liquid-solid interfaces and there are no tools for liquid-solid interfaces. We have all these tools for vacuum-solid interface, but there are no tools for liquid-solid interface, which are much, much more important. Why don't you use your inventive abilities to come up with tools that can study liquid-solid interfaces?” That was the best career advice I ever got.
So I’ve been waiting for you to say it as we’re developing this narrative of your budding interests in advancing human health, and it sounds like this is really the juncture where you were primed to get this kind of advice because it sounds like you were already asking those questions of yourself in terms of what you can do.
So then what’s your next move after getting this wonderful advice?
So then I messed around a little bit trying to develop assays for the liquid-solid interface. The simplest one was I was measuring the resistance of a thin film as I corroded it away, for instance, and some other false starts. But then when scanning probe microscopy came along…
And when you say it came along, came from where? What’s the history there?
Well, that’s kind of a… [Laughs] All right. It is kind of an interesting historical tidbit, if you like.
This is what we’re here for!
Heini Rohrer, who later won the Nobel Prize for the scanning microscope…
Heini Rohrer had done a sabbatical at UC Santa Barbara in Vince Jaccarino’s lab during the time I was there, and he noticed that I was there evenings, weekends, very hard worker, bright. So when Gerd Binnig invented the scanning tunneling microscope in his lab, he had the idea that this should spread. He was a very generous guy. He didn't want to keep it just in his lab. He wanted it to spread to the world, and he thought my lab would be a good place to help it develop because he liked what he had seen in me. So he sent Gerd Binnig here. The first talk in the world on scanning tunneling microscopy was actually in my group at Santa Barbara by Gerd Binnig on a way to a meeting in Los Angeles.
I thought, man, I can't get into this field, though, because here you have geniuses on a budget of millions of dollars at an industrial lab, you know. How could I possibly compete with that? Plus it’s ultrahigh vacuum, which I’d already had enough of. So then I started thinking, well, you know, I had been making tunnel junctions; maybe I could make mechanically adjustable tunnel junctions—so give up the idea of scanning a probe in three dimensions, but let’s just take two flat surfaces and press on them to bring them various distances apart. Maybe I could make that, because right then it came as…
Gerd Binnig and Heini Rohrer wanted to do inelastic tunneling spectroscopy. Now that they had done imaging, they’d like to do spectroscopy to identify the molecules they were imaging. I was the expert on that, and so that was the other reason he came, because they were hoping they could do that. I explained to him all the difficulties and why that was not going to work very well, and it basically hasn’t worked very well for the reasons I laid out, even though it’s been done in a few proof of principle kind of special situations. But it’s never become anything useful because of the problems that you need so much more stability in the positioning to do spectroscopy than you do to do microscopy. But I thought I might be able to get that with these squeezable junctions, and I was able to. So then I had a mechanically adjustable device, but what I noticed with that is you could not only operate them in liquid helium, but you could also operate them in air and in water. So I realized--
What’s the value of having those different media to work in?
Well, we get back to the ability to study the liquid-solid interface because now I have a liquid-solid interface that I’m studying. If I have the liquid inside the tunnel junction, I have two liquid-solid interfaces. So I got very excited about that and I built a scanning tunneling microscope that could image samples in water. That was the first one of those, and that was in Science magazine. I thought I could do biological molecules because now I was doing microscopy, and I felt that in microscopy, the most benefit to humanity had come from using these microscopes in medicine. So maybe these scanning probe microscopies could be used in medicine. So I kept trying to adopt the scanning tunneling microscope to do that.
My wife [Helen Greenwood Hansma PhD.] had joined my group at that time; she was a biochemist. We were trying to use the scanning tunneling microscope to image biomolecules, but that turned out to be a nightmare. But then the atomic force microscope came along. I actually had the original manuscript to review; I was the reviewer. It looked great to me, so I said, “Fine.” Then Calvin Quate, one of the authors, wrote me and he said he thinks there might be a mathematical error in that paper because someone told him that. He asked me if I would look at it more carefully. So I looked at it more carefully and sure enough, there was an error of a factor of 10 in one of the calculations, not that it affected the overall wonderfulness of the manuscript. But by that time, I had looked at it carefully enough to realize I’ve got to do this.
So then I tried to build those for use in air and I discovered all the problems. But then I had a guy doing gravity wave research in my lab because he was just a retired guy who wanted a corner of the lab. He was using optical lever to detect change in length of rods, and that wasn’t working out. But I thought, well, maybe this optical lever could be used to measure the deflection of a cantilever, and that turned out to be true. That gave the ability to do the atomic force microscope in liquids, and so now there was a powerful tool to study molecules on a surface under liquid. That’s continued to be… I mean that’s a huge research area now. I don't know… Lots of people are using atomic force microscopes to look at biomolecules on surfaces and stuff because it’s one of the highest-magnification techniques that you can have to look at functioning biomolecules.
If we could unpack the name a little bit, atomic force. Why is it called the atomic force microscope? I mean it sounds cool.
It sounds cool. It should rightly be called the scanning force microscope, but Gerd Binnig named it the atomic force microscope. The reason he did that was that he had the genius insight that you could make a mechanical cantilever, a macroscopic cantilever that had a spring constant that was smaller than the spring constant between two atoms so that if you had a tip on that cantilever and you dragged it up and over an atom, the cantilever would deflect rather than pushing the atom out of position.
Because you want to keep the atom in position? That’s one of the goals?
That’s one of the goals because you're trying to image a surface nondestructively. So he was saying that this microscope works down on the force scale of atomic interactions, so it was an atomic force microscope. It could measure the forces between two atoms. You’d have to ask him, but that was why I imagined he called it the atomic force microscope. And you know, some people have told me… [Chuckles] I’m a very loyal guy, and so I kept calling it the atomic force microscope even when it changed so completely from that original invention which used electron tunneling and cryogenic fluids. What I finally came up, after about 16 iterations with my co-inventor Barney Drake, used the optical lever at room temperature, with a three point kinematic mount, a compact head that held all of the optical lever components, an easily replaceable, indexed cantilever holder and many other features that became the basis of the first commercial instrument and the commercial instruments that followed. Some people felt I should have renamed it at that point and taken credit for it and said that the atomic force microscope was a wonderful precursor to it, you know, but now we have this and have a different name for it. But I liked Gerd Binnig a lot. He was a really nice guy. I liked Heini Rohrer. I liked that they had helped me out in the early days, and so I stuck with that name. I kept that name which was his name. So his paper then for many, many years got cited. It was always the first citation in my papers about atomic force microscope. So anyway, I kept it to honor him.
Now you mentioned… I’m intrigued. I was not aware that your wife was a partner to you in obviously more ways than one. I’m curious. In the early days when you're starting to think about the biological value of your research, are you relying on her a lot to understand biological systems and molecules in ways that you might not have had in your own education?
So you're clearly… You're taking your work home with you to some degree.
Absolutely. Yeah, very early on I had thought… I had had the arrogance to think that, well, look. I’m very good at math. I’m good at physics. How hard can biology be? I’ll just go ahead and learn the biochemistry I need to do biochemistry. [Laughs]
You sound like a physicist, I have to tell you! [Laughs]
That was so naïve, you know? [Laughing] Just incredibly naïve. Now after working with biochemists, you know, for all these…
Where did you meet? Did you meet at Berkeley?
Yes, we did. And now after working with biochemists for all these many years and biochemical collaborators and stuff, I mean I recognize that that was just, you know, the height of naïveté because what it takes to do biochemistry is so different than what it takes to do physics. There’s this huge body of information in order to be an effective biochemist, and you need to be able to remember things, for example. [Laughs] But yeah, so she was very helpful to me. It made for long days sometimes, but she was very helpful to me. We collaborated together. We had joint grants. We supervised students together. She became a research professor at UC Santa Barbara.
Now was the scanning ion conductance microscope an offshoot of the atomic force microscope, or that’s a separate endeavor?
Both. It was another scanning probe microscope like the scanning tunneling microscope and the atomic force microscope. It was yet one more scanning probe microscope, and it’s continuing to be used to this day. People who use it like to say that it provides the high-- I hesitated a little earlier in our conversation when I was going to say the atomic force microscope provided the highest resolution images of biological molecules and samples in action because the people who are continuing to do the scanning ion conductance microscope maintain that it’s higher resolution because it applies less force to the sample and doesn't deform delicate samples. So you can see features which you just can't see with the atomic force microscope because it deforms them.
But the problem with it is that you need a pipette and these pipettes end up being very delicate. So we worked for many years trying to microfabricate them and things like that. My guess is someday that’s going to happen and you're going to see that field take off when there are commercially available cantilever-based micropipettes. So it’s like an AFM cantilever, but it’s got a hollow channel to an opening right at the tip. Then that field will probably take off, but for the time being, it’s kind of… How to put it? It continues, but at kind of a low level.
So to return to this recurring theme of involving yourself in research that has practical value, right, with these microscopes, when does it first dawn on you that they will have commercial value and they will be sort of adopted and, I assume, sort of produced on a larger scale so that they can be used obviously not only well beyond your lab, but in places that have a direct impact on advancing human health? How does that process play out?
Well, the really decisive step on that was Virgil Elings came into my office and he said he thought that a scanning tunneling microscope could be sold, that it would be a good product, and he would like to start a company with me to make them. I didn't want to get involved in a company at that time. The academic climate was very, very different than it is today. Today, the idea of a professor involved in a company is like, “Yay! Wow! This is wonderful.” Back then it was like, “Look. You want to be a professor or a businessman? Take your pick,” you know?
“We’re academics and we’re not involved in business. That’s a totally different endeavor and it’s totally inappropriate.” So I was nervous about that and…
What about as a matter of intellectual property and patenting your research and making sure that you would retain…you know, not just that you might profit or not from it, but that you would retain some kind of control over how your research would be applied?
Yeah. Well, what happened there was when I was working on the scanning tunneling microscope, and when Virgil came to my office and saw it, I didn't think I had anything patentable, you know. This had been invented by the geniuses at IBM, the scanning tunneling microscope, and basically… Yeah, I didn't realize. I was wrong, but I didn't realize I had an invention and that the contributions that I had made were patentable. I didn't really realize that. I thought I was just kind of following in the footsteps of the IBM guys, and so I didn't patent that initial one. Then what happened was Virgil started making them and they were successful and he started selling them. Next thing I know, I am called into the chairman’s office and told that--
The chair of the department.
Of the physics department, and told that someone has blown the whistle on me and Virgil and that we are being investigated, that an investigator has been sent down from UC to investigate our potentially inappropriate behavior. So this went about a month--
Wait a minute. This is after your reaction that you're not going to get involved in the business side of this?
Right. Right, because I was still sort of involved in the business even though I was not part of it. I said I’d give him one of my home-built prototypes in exchange for one of his commercial ones when he made it. So I was helping him. So the complaint was that I should have patented the stuff, that I was giving away the University of California’s intellectual property inappropriately, which was correct—which was correct with 20/20 hindsight.
However, Paul, if I can stop you right there, you can't have it both ways. I mean if the academic and intellectual climate is there’s this stark divide between professor and businessman, right, how do you square that circle if you’ve made the decision that you're going to remain an academic and then the system gets mad at you because you're giving away trade secrets? I mean…right?
Right. I think it was fair. I got called in after a month and basically the chairman said to me that the investigation had concluded and that no action was going to be taken against me because I had made no profit in all of this. But in the future, be much more careful about patenting anything that’s patentable.
Were you made aware of a system that you should have gone through to have avoided this investigation in the first place?
Yes, that I should have patented it through the university’s office.
But my question is, were you aware of a system after the fact that you should have known about beforehand in terms of, “Hey, you're doing this stuff. Here’s the system that you should… These are the steps that you should take to go through.” I mean who dropped the ball in that regard in terms of not letting you know what that process was? Or was there not that process?
I think basically it was nobody’s fault but my own. When I signed up for the University of California, one of the first documents I signed was that I would dispose all intellectual property. I knew that there was an intellectual property office to patent things, but it just didn't occur to me that this was patentable. I didn't know enough about patents to realize this was patentable. I thought these other geniuses had invented the scanning tunneling microscope, and so I can't patent that. What I didn’t realize was that the many improvements I had made to make it a practical instrument were patentable. So at any rate, I was just kind of slapped on the wrist and told, “Be more careful in the future.” So then I was more careful in the future, and I did patent the design for the atomic force microscope, which became the first commercial atomic force microscope. This illustrates my earlier point that my contributions to what I continued to call the atomic force microscope were substantial – and patentable. That patent did generate more patent royalties for UC than any other invention until the blue laser came along.
Wow. Wow. Do you have some rough idea of numbers in terms of revenue?
I mean millions of dollars? We’re talking significant money?
Oh, yeah. Yeah. I think somewhere…$10, $20 million, something like that.
Yeah. Yeah. What kinds of research environments was this technology adopted? I mean give me a sense of who’s taking these ideas, what kinds of people are using them, and to what ends are they using them for?
Well, there were two distinct markets. The one market was industrial where people wanted to use these microscopes to look at their manufactured products, and scanning tunneling microscopes from Digital Instruments were very useful in the early days of compact discs, for example. They allowed people to see the shapes of the little structures that they were making on the surface of the compact discs with a clarity that was impossible before. Then it’s continued now into the semiconductor industry. There are atomic force microscopes on production lines of integrated circuits and so on to do quality checks and monitoring, and also for development of new integrated circuits and magnetic hard drives. They became very useful for that because they could image the magnetization patterns on hard drives even as the little magnetized spots got very small. Basically, you’d use a magnetic tip on the cantilever and you could sense the magnetic field of these little magnetic domains.
Then in the academic world, a lot of people were interested in potential biological applications of this—you know, a microscope that can image biological samples at high magnification in fluid, which I mean, you know, you had the light microscopes that could image in fluid, but not at high magnification. You had the electron microscopes that could image at high magnification but not in fluid; you had to dry things out. So this kind of gave high magnification in realistic environments. I don't know all the other applications right now, but those were the ones that were of most interest to me.
Beyond your wife, and particularly in the health science applications, who were some of the people that you might have collaborated with so that you could gain a better understanding of what your invention would be good for? I mean were you talking with clinicians? Were you talking with other biologists who were working in research environments like places like the NIH or pharmaceutical companies? I’m curious in terms of your direct connection to the people who worked in these industries.
My main collaborator, in addition to my wife, was Dan Morse, who was a marine biologist at Santa Barbara, and he was wonderful. I loved collaborating with Dan Morse and Galen Stucky, who was a chemist. Those two guys were great. We had these joint meetings trying to understand the origin of the strength of abalone shells, and basically I ended up building multiple microscopes, including using the scanning ion conductance microscope to kind of figure out the intricacies of why abalone shells were so fracture-resistant. Then Herb Waite also joined that effort. So those three guys were amazing collaborators. I also had wonderful biological postdocs including Ratnesh Lal, who is now a professor at UC San Diego.
Yeah. So you really did not go beyond the campus environment in terms of working with scientists in other institutions.
Not really. A lot of people came to Santa Barbara to use the microscopes. I had one graduate student who worked with them when they came. He graduated. I forget how many papers. He had something over 20 because all these people would come with their samples and we would look at them for them. Basically, they would use that often to write grants to buy microscopes of their own. So we did a lot of that. We did a lot of, you know, letting people come and run their samples on our microscopes to see what would work out. By far my best collaboration of this nature was with Hermann Gaub, an amazing scientist from Germany. I was so impressed with him that I gave him one of my AFM prototypes to take back to Germany with him. I later spent a sabbatical with him. But I never had an extended biological collaboration with these microscopes. I had a wonderful collaboration with a man named Bob Coleman at the University of Virginia on layered structures, and that was partly because I wanted to go to Virginia to work on the lights for the Light Of Truth Universal Shrine that was being built there. So I did a sabbatical where I did those two endeavors.
What was your interest in doing that sabbatical?
I wanted to help them have the light in the Light Of Truth Universal Shrine. I wanted to help them build that light. Also, we knew that for the scanning tunneling microscope it was not useful really for biological samples, but it was really useful for atomically flat conductors that you could peel like graphite. Well, Bob Coleman had a desiccator full of atomically flat samples you could peel like tantalum diselenide, tantalum disulfide. He was a long-term friend of mine, and basically he was pleased as punch to get images of these surfaces. We imaged charge density waves on the surfaces, which had never been imaged before, little mounds of charge on the surface. So that worked out very well for both of us. We even got a mention in the National Enquirer.
Now just to get the narrative correct, have you remained involved in scanning tunneling microscopes over the course of your career?
So when did that end?
As soon as the atomic force microscope came in, I was done with the scanning tunneling microscope. I recognized that that instrument was not useful for my purposes. I think we might have built one more for Bob Coleman just because he was a friend and he wanted one that worked in liquid helium, but basically I was totally focused on atomic force microscopes once that became a possibility.
For atomic force microscopes, have you remained involved? Are you interested in the ways that they’ve been applied, perhaps in ways that you never even imagined yourself?
No; yes. I’m not involved myself anymore. Basically what happened was I ended up building about 40 of them in my lab with Barney Drake mostly, and by this time companies were involved. Digital Instruments was very successful and then Asylum Research started. My students started that. Basically, microscopes became very sophisticated. The last two postdocs I had working on microscope development were doing sophisticated finite element analysis for the designs of things and all kinds of simulations and stuff for the damping and this and that and the other thing. It got very, very technical -- engineering, basically. It became much more an engineering project than a science project, which is my main interest… You know, I kind of make that division that the physicist is going to come up with something that hasn’t existed before, but then if that something turns out to be useful, the engineers are going to make it useful. The engineers are going to make it work really well.
And it became that. I mean, basically, in my view, Atomic Force Microscope development is now mostly enabled by engineering approaches. And I was never really interested in Atomic Force Microscope applications except as a way to justify more building because that’s what I like to do, build.
And basically, the field got away from me. It was like there were all these engineers and all these companies that were very sophisticated, you know, and it didn't seem like I had much ability to contribute anymore, really.
Right. So to the extent that you were aware of the ways that engineers adapted and improved the technology, what are some sort of topline examples of the ways in which this technology has been adopted by industry and by research institutions?
Let’s see. Are you more interested in how are the instruments improved or in the applications?
In the applications. Basically, as a result of the improvement to the instruments, in what ways have they been applied?
Well, there’s a lot of micromechanical work these days where people are using instruments not only to image, but to measure the mechanical properties of surfaces and polymers and trying to understand the behavior of polymers by analyzing the micromechanics of mixtures that segregate, for example. That’s become a big industry. And in the biology, it’s become a big industry to look at the shapes of proteins and how protein shapes change as proteins function and to see… And people are looking at DNA processes. People are looking at DNA origami. People are looking at how DNA comes together, how loops open in DNA and close in DNA and a lot of… People are looking at antimicrobial peptides, for example. One of my former students, Georg Fantner, who I think is kind of at the head of AFM development in the world in terms of academics—he has been working on antimicrobial peptides as an alternative to antibiotics because you don't develop the same kind of…
…resistance with these antimicrobial peptides. So he’s been studying the mechanism of action of the antimicrobial peptides. But basically, I’m a little bit out of the field. I don't go to their conferences anymore. That’s kind of two fields ago for me. I first went through bone, and now even bone is gone for me. I’m really focused on chronic pain now, so I don't pay much attention to scanning probe microscopy anymore. I mean I got invited to give a plenary talk a couple years ago, that 2018 one I sent you, for a scanning probe microscopy conference. So I got in contact with a little bit of what’s still going on in the field there, but basically I’ve moved on.
So we’re at a narrative turn in your career here, so it’s important just to orient ourselves with the chronology. When you start to move away from microcopy, roughly what years are we talking about here?
This is going to be like late ’80s?
That sounds about right. I mean I could screen share and pull up my publication list. That would probably be the best place to look for that, or you could…
But basically, my memory is not going to be good compared to looking at my publication list and just see when the topic of the papers change.
Sure. Okay. Well, I guess of more relevance in terms of a matter of intellectual history, when did you know it was time to change course and what was available to you in terms of thinking about what to pursue next?
Well, I had been working on these abalone shells trying to decide what made them strong and…
And is this with your collaboration with the marine biologist that you referenced previously?
Exactly. I had also spent a sabbatical with Hermann Gaub, who was a wonderful expert of atomic force microscopy and inventor of new things to do with it, such as pulling on molecules. I had been spending a sabbatical with him learning about pulling on molecules, and anyway, using that technique I discovered the principle of sacrificial bonds and hidden lengths, which was then… And then I started wondering, well, this seems like a very general principle, and the editor of Science, Philip… What was his name? He was an editor. Philip Glass? No. Philip Ball. Philip Ball. Do you know him?
I don't. No. No.
Incredibly brilliant guy. But anyway, he titled my paper “ Molecular mechanistic origin of the toughness of natural adhesives, fibers and composites”. He was really on the ball because we were doing it in terms of the abalones, but he was thinking this is probably much more widespread, and he was absolutely right. I thought, well, if this principle is so important in abalone shells, I wonder if nature uses it in bone? So I looked for it in bone with the atomic force microscope, pulling on molecules, and discovered it in bone. So then that was a Science paper, and that really started my interest in bone because then the interest was, well, if these molecules are important, where are they in the bone? Where are they and how do they work in the bone? So I--
So Paul, I’ll ask you at this juncture to come back to this idea of suffering from a degree of arrogance or naïveté about understanding biological systems.
When you enter this wide world of bone, do you avail yourself of working with people in bone biology or are you just sort of being an autodidact with this also?
Autodidact? Does that mean I did it myself pretty much?
You taught yourself the science of bones.
Yeah. You know, I got all these books on bone out of the library. At that time, you got books out of the library.
I had a stack about 4 feet high. [Laughs] This is funny. When I first got in the field, I was talking about this at some conference and I was saying, “And I read this big stack.” I realized as I was speaking that it was not really true and corrected it to “Well actually, I kind of scanned it.” That got a big laugh! [Laughs]
I looked at a lot of literature in bone and there one guy, Stephen Mann, who was friends with Dan Morse, who was an expert in bone, and he had come and given a talk on bone at Santa Barbara. I interacted with him some. I even went to Israel to give a talk. So I learned some about bone from him as well as his papers. Later on I met many wonderful researchers including Simon Tang, Jeff Nyman, Mary Bouxsein, David Burr, and Mitch Schaffler who did fundamental research and Adolfo Diez Perez and Sundeep Khosla who did clinical trials.
Now in terms of your motivations, right, are you getting more specifically interested in applying your expertise to making useful stuff to help people at this point, or that’s still coming later on?
No, that’s a major factor here because I was telling people, “Look, I got into this atomic force microscopy in large part because of biological applications.” I remember telling one group at an after-dinner talk at an AFM conference, “You know, what I really want to see is I want to be able to have a picture on my wall of a person that has been helped by the atomic force microscope with a medical problem.”
You know? All of these papers about “This is the way the molecules fold” and all that—that’s good, but I want to see a picture on my wall of someone that’s been helped.
Did you ever receive that satisfaction with AFMs?
Strangely, it just happened! The picture is of my beloved wife, Pamela Benham, and she was helped by some research that used an AFM to study the effects of cola on dentin. It had great images to show how brushing too soon after a cola drink exposed channels in the dentin that are known to contribute to tooth sensitivity. The clear AFM images of the channels really motivated her to work on the problem with products designed to minimize sensitivity. Also it might happen with bone fracture. Bone fracture is a huge problem and it’s a major, major factor for quality of life. It really decreases a person’s quality of life if they get a hip fracture.
Sure. Or it kills them, even.
Or it kills them. So I thought, well, if I could help prevent bone fractures, that would be something.
So that was my motivation to go into that, to try to prevent bone fractures by pointing out that there was this other component to the fracture resistance of bone. It wasn’t just how much bone you have, which is what DEXA measures. So all the kind of diagnosis of bone fragility these days is done by way of x-rays, most commonly DEXA, and that measures how much bone you have. So they talk about if you have had bone loss, and so if you have too much bone loss, you're given a drug to cure the bone loss problem. Well, what I had realized was there was more to bone fragility than bone loss. There was also, you know, how soft is the bone?
Right, right. And how do you quantify how soft bone is?
And how do you quantify that? So once I started studying bone and I discovered these molecules and I thought they were important for the fracture resistance of bone because they were very important for the fracture resistance of abalone. So I had a paper about that, Nature I think, and I got invited to a bone conference in… Where was that one? Rome. A bone conference in Rome. So this was good. Okay, yay. Now I get to see bone folks. I gave my talk and--
Who are the bone folks? Are you the only physicist there? I mean, I assume the rest of them are in the biological world, right?
Mostly. There are some engineers that have studied mechanical properties of bone. There are some engineers, but mostly it’s medical people.
So any rate, after my talk this distinguished professor named Adolfo Díez-Pérez came up and he said, “I really enjoyed your talk, and I think you're right. I think that the amount of bone glue may definitely be a factor in fracture risk. It’s part of a larger concern about bone quality as opposed to bone quantity. But you have to realize your results are clinically irrelevant.” I said, “Clinically irrelevant? That’s interesting. I mean, I thought bone fracture was a big problem, and so what were the origins of bone fracture seem very clinically relevant to me.” He said, “No. It’s clinically irrelevant because anything you cannot measure in a patient is clinically irrelevant. There’s no way to measure this in a patient, and if you can't measure it in a patient, it’s clinically irrelevant.” So that kind of sat in my mind, you know. Okay…
How do I prove this guy wrong?
How do we make it? How do we measure it in a patient? So how do we make a measurement in a patient?
The other question, I think, that would have to come up here is, particularly as you're measuring bone quality as people get older, what are the sort of upstream advice in terms of lifestyle that might prevent this loss of quality and quantity from happening in the first place also, right?
Right. But there again you want to be able to do it in patients. You want to see patient does exercise. Does that help or hurt the bone quality, you know, and you need to be able to measure it. So it was kind of in the back of my mind—how in the heck would you measure this in a patient? There were a lot of people measuring bone quality in pieces of bone. Engineers measure bone quality all the time. For example, they’ll take a piece of bone and they’ll put it in a four-point bending apparatus. They’ll see how much force they have to apply till it snaps, you know? They’re going to see how elastic it is and how well it recovers after being bent. They measure all kinds of mechanical parameters on bone, and so there’s a huge literature about the mechanical properties of bone. But you can't do three-point bending in a patient! [Laughing] You can't take their leg and break it to see how resistant it is to breakage, you know? So none of these techniques were suitable for use on patients. So I was imagining what in the heck… How would you measure something relating to the quality of bone in a patient?
So then I had this NSF grant that I had submitted that I had had for many, many years. It was another renewal about AFM that I didn't have all that much enthusiasm for. It came back rejected because I hadn't had enough community outreach in the proposal, that I had made no mention of community outreach, and that was a required section. So I thought, okay, I’m done with electron tunneling. I’m done with microscopy. I’m going to try to make that instrument to measure the bone.
And this is a totally new technology now. You're not really relying on your expertise in AFM. This is a brand new world in terms of instrumentation.
Brand new world. So I went to the supermarket and I bought some soup bones. I knew that if you baked bones, you could degrade their quality because you degrade these molecules we called bone glue. You're not changing the amount of bone, but you're changing its quality if you bake it. So I baked it at various temperatures in my oven at home and oh my god…
And we’re talking a dry bake. We’re not talking braising.
Dry bake, and the stink from that—oh, man… In fact, it ruined the oven. But anyway, now I had some bones and sure enough, you know, I had a sledgehammer and I would let it fall because I wanted to simulate something more natural. I didn't really want this slow bending because bones don't fracture with slow bending, you know.
You’re talking about like a sledgehammer that replicates an old person falling down steps.
Yes! So I had that and I noticed that for a bone that hadn't been baked, I could raise that sledgehammer all the way and I’d have to hit it several times, but by the time it had been baked a lot, I could raise that sledgehammer just a few centimeters and let it go and the bone would break. So now I had--
Now what is baking telling you about biological processes where obviously people are not subjecting themselves to 400-degree ovens? What is that telling you?
It’s telling you that organic molecules are important for bone strength, not just how much calcium you have, not just how much mineral you have. It’s not just--
So this is the quality issue, not just the quantity issue.
The quality, exactly. It’s not just how much mineral you have; it’s how well that mineral is stuck together, basically, with the bone glue. So at any rate--
Yeah, and Paul, I want to ask at this point the bone glue, do your colleagues buy this concept of bone glue? I mean bone glue—is this your thing or is this accepted that it’s something that actually exists?
Well, let me put it this way. We put an article into Nature Materials and the editor, on the cover, said bone glue. The editor came up with that word, bone glue. [Laughing] We had never used that term, but I loved it. I loved it, bone glue, because it is so descriptive.
So I’m very grateful to that editor, as I was to Philip Ball earlier. We just started using that term.
And is there something unique about bone glue? I mean, right, all molecules in all parts of the body are somehow stuck together. I mean, is there heart glue? Is there lung glue? I mean is there something unique about bone that gives it this concept that you're conceiving at this point?
Yeah. The one thing about it is that those other tissues that you mentioned are soft. Bone needs to resist deformation, unlike a heart which can be squeezed. Bone, you don't want it to bend too much.
You want to be able to walk on it. So people already knew that bone fracture proceeds by little tiny microcracks opening in bone and that everybody has microcracks in their bone at all times. You do; I do. All bones are filled with microcracks. But the thing is there’s something that keeps those cracks from growing, and that’s this, we believe, bone glue basically that’s the organic glue that sticks them together and resists their separation even at a distance.
So the way that the sacrificial bonds and hidden length mechanism works is that you have a polymer molecule between the surfaces and as you try to separate them, you have to work against entropic elasticity, which is a lot of work. Then before you can break the polymer, a little folded module of it will unfold, making it slack again, and so then you have to stretch it again and another one will go. These sacrificial bonds open up extra hidden length which you then have to stretch, and the work to stretch that can be 100 times greater than the work it takes to break two atoms apart.
So it’s like the difference, in fracture resistance, between a diamond and an automobile tire, right? The diamond has all these very strong bonds, but if you hit it with a hammer; it shatters. Take an automobile tire. You can beat on it all day long, right, and it’s not going to shatter, and it’s because all of your energy is not involved in breaking bonds. It’s in this entropic elasticity of stretching molecules that recover.
So basically the concept of bone glue—I mean once people heard it in the field, they accepted it. They understood it, you know. I talked at bone conferences about it. Nobody ever objected to the term bone glue. They got it. They didn't know what molecules it was and I wasn’t sure either. I’m still not absolutely sure. We have a lot of ideas about what those bone molecules are, probably highly phosphorylated proteins like osteopontin but nobody’s sure what they are. There aren’t good assays for anything like that, but the basic concept that there are organic molecules sticking together the mineral pieces, that’s, I would say, very well accepted by people in the field.
I’m curious if you ever looked at how cranial bones in babies fuse during the first years of life and if that was ever fascinating to you in terms of learning how bones fuse together and what kind of glue might be involved there.
It sounds interesting, but no, I never investigated that.
Okay, all right. So in terms of developing the instrumentation and setting out your research goals, how do you go about this?
All right. So now I have two pieces of bone that I want to distinguish in a human body. I have degraded bone and strong bone, and I wondered how in the heck could I distinguish those two if they were inside a human body? I messed around with various things, but then finally what I came up with was like an automatic center punch. Have you ever used an automatic center punch?
Okay. So I noticed if you took an automatic center punch, on the good bone it would make a tiny indent. On the bad bone it would make a deeper indent. I thought okay, this is promising, but the problem for using this on a person is that you have to be able to measure the depth of the indent. Maybe you cut a little slit so you put the automatic center punch right on the bone, but then you’ve got to look at the depth. You’ve got to see how deep it went in, and that would be a problem in doing that in a body.
So basically, to make a long story short, what ended up happening was, after a lot of false starts and building elaborate instruments and simple instruments, we ended up with something that’s like an automatic center punch that measures the distance the tip goes when it clicks. So that’s put on the surface of the bone of a patient. There’s basically a fine tip about like a hypodermic needle that’s put down through the skin. That rests on the surface of the bone and you press down on it and it goes pop. It measures how far the tip goes into the bone very precisely. Basically, if the tip goes far into the bone, the bone is soft, poor quality, and if it goes only a small distance into the bone, the bone is of good quality. The commercial instrument for this is named the Osteoprobe and it is sold by Active Life Scientific, which was started by my former students and others here in Santa Barbara.
And this work is in pursuit of trying to figure out that original question of how do you determine the clinical value of this research?
Yes, and beyond that determination of clinical value, the idea is you have huge numbers of women who are getting bone density tests because they wonder if they should be taking anti-osteoporosis drugs. Now what happens is if you take that test, you're divided into three classifications. The first classification is normal. The second is osteopenia which means you have a little bit of bone loss, or osteoporosis which means you have a lot of bone loss. Now for the physician for normal and osteoporosis it’s easy to know what to do. For normal, nothing is needed. No treatment is needed. For osteoporosis, there’s so much bone loss that the physician will recommend a drug to like Fosamax or denosumab or one of the many other drugs are available. The patient may or may not choose to take it, but for the physician, it’s clear: the physician recommends that the patient take the drugs if they have osteoporosis.
Now the problem is that the majority of hip fractures in the United States happen in the osteopenic population because there are more people there, and in that case the physician really doesn't know what to do because these drugs have bad side effects. You know, should I give the patient the drug or shouldn't I give the patient the drug? This is difficult for physicians. So the idea is, for the people who are in this population, test them with the Osteoprobe. So we know they have some bone loss—not a lot of bone loss, but some bone loss. Well, measure the bone. If it’s of good quality and they have some bone loss, then you say, “Okay. You probably don't need drugs.” On the other hand, if the bone is soft, of poor quality, and you have some bone loss, then you say, “You need drugs.” So this would be the long-term dream of mine, which would be that this could be used to prevent bone fractures by letting physicians and patients have a better idea of their bone health leading to the ability to make informed choices of suitable therapy to prevent bone fracture.
Did you get involved in either the therapies in terms of the drug makers and why the particular drugs that they make are useful for patients with bone loss?
To a limited extent. I went to Lily. I went to Amgen. But the focus of those drugs has been, understandably, based on what you can now measure clinically and what you can measure now (June 2020) is DEXA. So the focus of those drugs is on bone loss. How much do those drugs build up the bone? Although it turns out that some of those drugs actually do help cure soft bone as shown by Adolfo Diez Perez and his team with the Osteoprobe. Right now, (June 2020) the Osteoprobe is in the final stages of a long FDA approval process. Once it is approved it will be exciting to see what happens!
The dream is that the instrument could become in widespread use and prevent a lot of bone fracture. When I was in Barcelona we were doing some of the first tests I saw an entire floor of the Hospital Del Mar devoted to people, mostly women, who had suffered a hip fracture. They were lying on their backs, some with a leg elevated for weeks! They couldn’t turn to their side or change their position. There were more elderly women there with hip fractures than from all other causes combined. We had more trouble finding normal controls than cases! This is a giant problem. Lots of human suffering. I really hope that the Osteoprobe can help decrease hip fractures, not only from allowing physicians to make better decisions about drugs, but also by helping us learn what exercise, what diet, what supplements, whatever can help prevent or reverse bone softening.
Speaking of Barcelona, a kind of ironic thing is that the same distinguished physician, Adolfo Diez Perez, who told me that my research was not clinically relevant did the first clinical trials! I was giving an AFM talk in Barcelona, the same one where I mentioned that I’d like to have a picture on a wall of someone I’d helped. Adolfo Diez Perez was in Barcelona, so I went to talk to him about my progress on making this bone diagnostic instrument. He was so excited. He wrote a grant over the weekend and he started doing the research. He’s led the worldwide research effort on that instrument, published many papers, and all that kind of stuff. He’s been a wonderful collaborator.
Now have you ever pursued yourself or worked with collaborators who looked at the genetic basis for why some people experience bone loss and bone quality over a period of time and others do not?
No. No, I have not. Again, the thing is you have to realize I’m not so interested in using instruments. I’m interested in building things. I mean, that’s what I’m good at, and I’m no better than anyone else at trying to figure out mechanisms of genetic effect. I mean, that’s one of the things I’ve learned from collaborating with biologists and physicians, right? I mean, they are very, very bright people who can figure out good experiments. What I can offer them is building better gadgets. [Chuckles]
Have you learned… I mean, it’s a similar kind of question that obviously you’ve been adjacent to with your own research, but what about some of the lifestyle choices that people make? I mean diet and exercise—have you found, or at least in reading the literature, that those things do make a difference with regard to bone quality?
Well, the problem is there have not been experiments on those things. I’ve been praying for the experiments to be done on that. I mean I’m a little bit out of contact with that field too, I should say, because I’ve been in the field of chronic pain for about the past, I don't know what, five or ten years. So I’m a little bit out of contact even with the bone field, but I was always pushing for that and praying for that, that people would do exactly that kind of thing, you know? Do an exercise study. Measure people before and after an exercise program. Measure people with different dietary choices, you know? I would love to see that research. I would love to see that research done because I think it could really help a lot of people, but the problem at the moment is getting FDA approval for the instrument.
Now in terms of your satisfaction that these instruments should be widely adopted, right, what’s a target where you would say, you know, “I’m thrilled where this is”? This has really been adopted, and people really now, on a wide scale, have access to this additional diagnostic tool for determining their overall health. Where is that relative to where you’d want it to be ideally?
Well, it’s nowhere right now because the only way a person can be tested is be part of a research program. Where I would like it to be would be that every woman or man who has osteopenia would have the ability to have this test.
Mm-hmm [yes], mm-hmm [yes]. But in terms of getting that done, you see these as regulatory and policy processes and this is sort of out of your realm? Is that the basic challenge there?
How do you hand this off? Who are the people to hand it off to so that these things do come to fruition?
Well, in the case of this instrument, there is a company that I was one of the founders of called Active Life Scientific, which is marketing these instruments. They’re continuing the marketing efforts and getting the FDA approval. They got it CE-approved in Europe, and they’re on the path to FDA approval. Then this COVID hit right when they needed to do one more clinical test to satisfy the FDA, a small study.
It was a crazy thing because the FDA was concerned about safety. Well, there have been 3,000 people tested so far in the world, and the only thing that’s gone wrong is one person got a skin infection. That was easily cured with antibiotics and that’s been it. But there was never a safety study in the United States done in consultation with the FDA.
There was a safety study done in Washington, but it didn't satisfy the FDA. Then there was one done in the Netherlands, but that wasn’t Americans. So now the FDA is insisting that there be at least a small FDA-approved study design safety study for this instrument, and that’s what’s holding up the FDA approval because now (June 2020, Covid) you can't do medical tests. Like at Santa Barbara, all medical experiments have been discontinued except for those that have a direct potential benefit to people’s health. So things like this, which is just for intellectual value of is this thing safe, that doesn't directly help the patients who have been tested—all that’s been suspended. So unfortunately, Active Life is just kind of treading water until they can get over this last remaining hurdle from the FDA.
Yet another casualty of coronavirus.
Yes! I’m kind of interested in it from a distance. But I know enough about myself to know getting involved with the FDA in studies and regulations and insurance company reimbursements and all that kind of stuff is neither my talent nor interest.
Mm-hmm [yes]. Now to stay on track with the chronology, what comes next? Do you start to pursue neurodegenerative diseases or is chronic pain the next item that you tackle?
Pain comes next. Basically I had chronic pain myself for about five years.
Could you trace it to a particular injury?
Yeah. What happened was I had a big bougainvillea tree in my backyard and one day I decided it was time to really trim that down. It was an incredible amount of effort, and by the end of the day, my elbow was hurting. It had gotten quite sore during the day, but I just kept going. By the end of the day it was very sore, and it continued to be sore for the next few months. I had cortisone shots and I did physical therapy and so on, but it wasn’t getting better. Then finally it seemed like it was getting a little bit better, but then the shoulder on that side started being very, very painful.
Probably because you were favoring particular movements?
Maybe. That’s what I told myself. So then I was using the other arm more, and then the other shoulder became very, very, very sore. So by the end of the five years I was no longer machining, which I love, because I couldn't turn the knobs of the milling machine and so on. I wasn’t reaching over my head to do anything. All gardening was gone. I was sleeping with five pillows. You know, I was really disabled by the chronic pain.
Then Brian Chang, a wonderful man in Asia, said, “Put your arm in a sling for three weeks.” So I was desperate. I mean I’d been doing physical therapy for five years, but I figured okay, I’ll do this instead. So I put my arm in a sling. But I was used to working on the problem of my chronic pain every day because I used to do the physical therapy every day. So I decided I would start looking on the Internet about chronic pain to see what I could find out. What I found out was revolutionary to me. I had no idea how chronic pain worked, and I was just amazed.
Basically then I started reading books about it and realizing that it was a creation of my own mind. It was my own mind being overprotective, trying to protect me, but actually harming my ability to function. Once I learned that, then I learned techniques for retraining your brain away from pain and did it. So I recovered from chronic pain and then started teaching those techniques to others and figuring out what gadgets could be built.
First, I was just teaching people what I had learned about how I had recovered from chronic pain, and then someone asked me in one of my first big talks on it. He said, “Why are you doing this? You're a builder. Why are you giving talks about recovery from chronic pain?” and I said to him, “Well, you know, the thing is I want to learn enough about chronic pain to decide where there’s a building opportunity”. That’s what’s happened. I found some building opportunities that I’m building in response to.
What are they? What are your building opportunities in response to chronic pain?
Well, one thing I’m working on is a pain meter that will objectively measure chronic pain because one of the problems with chronic pain is that there is no instrument to measure. It’s kind of like bone quality. You know, there’s no instrument to measure it, and this is a problem in many ways. For example, it’s a problem because doctors don't trust patients’ self-account of pain, but they have nothing else. They think maybe the patient is just there to get opioids or you know? They try to make assessments. You know, is the person really in pain? Or they say, “It’s all in your head,” which is very funny because at the same time it’s true and insulting and very unhelpful because--
But, Paul, when you say it’s true—to go back to you trimming the tree and your elbow hurting, right, if you put your elbow under an x-ray, right, aren’t they going to find that there’s some loss of cartilage or a strain on the tendon or something like that that shows that there is a physiological source for the thing that’s registering as pain in your brain? Right?
So it’s not just all in your head.
Yes and no. [Laughs] What happens is signals go up from sensors that are in your body, right? They go up from these sensors and they go into your spine. There’s some filtering right in your spine, and then the signals go up into your brain. Now right now your brain is receiving signals from all the sensors in your body, right? Now until I mentioned this, you weren't aware of the force of the floor on your feet, but now that I mention it, you notice, “Yes, I can feel the force of the floor on my feet.”
You weren't aware of the position of your arms necessarily until I say it, but then you can be aware of it. There are all of these things—the temperature of the room, the brightness of the room, the forces on various parts of your body. There are all these things that are sensory signals that are going into your brain and your brain is saying, “We do not have to pay attention to this. I do not--”
Because it’s just too much to…
Yes. Speaking as the brain, “I don't have to bring this into my person’s conscious awareness” Conscious awareness is very, very limited. Most neuroscientists believe that you can only be conscious of one thing at a time (though you can cycle through 5 or 6 so rapidly that it appears you are conscious of 5 or 6 sometimes). This is a very small number compared to the thousands of signals to your brain from your senses. Your unconscious mind is a supercomputer. It’s handling all of these signals, making all these decisions about is this dangerous? These signals coming to my brain—are they dangerous or not? It’s making these decisions and if it decides that signals that are coming to your brain are dangerous, then it lets you know by creating the experience of pain at the origin of the signals and putting it into your conscious awareness. Your unconscious mind creates the experience of pain by activating neural circuits in the brain that generate the experience of pain, and then referencing it to the somatosensory cortex which then makes it felt in a particular part of your body. So if the signals are coming from your wrist and the brain decides, “This is dangerous,” it generates the experience of pain, references it to the wrist on the somatosensory cortex; you feel pain. So the pain is a creation of the brain that’s an appropriate response to signals coming from your hand. That’s acute pain.
Acute pain is wonderful. Acute pain is important. People without acute pain die young. They bite the inside of their mouth and don't even know it and things like that. So acute pain is very useful, but what happens is that if the brain generates the experience of pain for three months or more, it gets good at it, just like riding a bike, right? Neurons that fire together wire together. Basically the brain gets very good at generating the experience of pain, and it has a sense that this is a dangerous place for you. This is dangerous. We’ve got to be careful of the shoulder (in my case). We’ve got to be careful that we don't lift too high, that we don't do too much, right, because it’s dangerous. This is a hurt part of our body. So even when very small signals go up to the brain, which in the past it would have said, “This is nothing.” It would have ignored it, right? But now it’s sensitized. The brain is sensitized that this is a problem area, and so those small signals come up and the brain says, “Pain, pain, pain, pain. Danger, danger, danger, danger.” So the pain continues even after the body has healed. So the physical body heals, but the pain continues, and that is chronic pain. That’s chronic pain. The body heals, but the pain continues.
So you're convinced that with your elbow, for example, your elbow was still registering pain long after a physician could have looked at your elbow and said, “Sorry, Paul. There’s nothing wrong here. Your elbow is fine.”
Yes. Or they might have seen some inflammation, which the brain does also. Basically, if the brain feels that this part is at risk it can cause inflammation. Like my shoulder, when I went to the physician, he diagnosed bursitis. Bursitis. Bursitis is pain and inflammation, the point being if you're experiencing pain in a region of your body, then your brain wants to protect it by padding it. So it adds inflammation, extra fluid. So they could see that extra fluid and the diagnosis is bursitis. Bursitis. [Laughs] But the bursitis was caused by the fact that my brain was being overprotective. And then the bursitis itself caused a little bit of pain, so you get this kind of feedback. That’s why it was good to put my arm in a sling, because it could interrupt this kind of feedback with the confidence that I have not done anything to injure the arm that was protected by the sling.
Is that to say that all inflammation has a neurological origin?
No. I don't know enough about inflammation. I would be very surprised if that were true.
I suspect there are many origins for inflammation beyond that.
Okay, okay. All right. So to get back to your research, right, instrumentation, studies—what’s your game plan now that you’ve got yourself thinking about yourself as a patient and how to help other people besides yourself?
So one of the things that turned out to be very helpful for the people was learning how to overcome chronic pain. Like I sent you that outcome sheet from my chronic pain recovery group. I don't know if you had a chance to look at that.
You saw that people were quite happy with it, that it was good.
One of the things they used was a gadget that we made in my lab, a biofeedback gadget. The biofeedback gadget was a fancy thermometer that you’d hold in your hand, and you could learn to warm your hands. You learn to warm your hands with your mind. Did you know you could do that?
I did not.
You can, and you can learn the technique relatively easily, especially if you have a very sensitive thermometer, which is what we gave them—something where it will respond to like a tenth of a degree change because then your brain can learn how to warm your hands if you can see what you're doing. Warming your hands turns out to be very useful for recovering from chronic pain—learning to warm your hands with your brain.
In the first place, it graphically demonstrates the control you can gain over things you wouldn't imagine you could control just with retraining your brain. Like controlling the temperature of your hands. Like controlling your chronic pain. At first you might not imagine that that was within your capacity, to develop the capacity to change your hand temperature or change your pain. The hand temperature is the easier one, but fortunately, it also has another benefit which is…
You know there’s fight or flight. I don't know how much you know about that, fight or flight, parasympathetic/sympathetic nervous system activation. Well, that was a wonderful evolutionary development to keep people safe. You know, you see a lion and you get into fight or flight mode. How does that work? Well, what it does is it puts more blood in your muscles so you can fight or flee. So you have more blood in your muscles. Well, that mechanism is still very common, but it’s not effective anymore because most of the problems that you encounter in your life that stimulate this fight or flight…
They’re not lions.
Exactly! They are not helped by blood in your muscles, right? And people, especially nowadays with COVID and all this kind of stuff, they read about problems and react oh my god, oh my god, COVID…running out of ventilators… Oh man, oh man, oh man. So all this fear gets generated and the body goes into fight or flight. The body goes into sympathetic nervous system activation because it sees a threat. It recognizes a threat, and so it puts the blood in the muscles.
Well, the problem is where does it get the blood? It’s not going to create more blood right away; it’s got to get the blood from non-muscled tissues. So the hands are an example of non-muscled tissues. It takes the blood away from the hands. Unfortunately, also a lot of the internal organs are non-muscled tissues, so it takes blood away from them. So long-term this is a bad thing to be in fight or flight all the time because you deprive the blood from organs that need it! And your hands are cold.
But you learn to warm your hands. The only way your brain can warm your hands is get you out of fight or flight, so basically you're learning how to get out of fight or flight. For different people, different techniques work. For some people, it works very nicely to put a hand on the heart and say, “I am safe. I am safe.” Have you ever done that?
I have not, no.
Try it right now. Just put your hand on your heart. It’s as good as a hug, people say, and now just say to yourself for just a few seconds, “I am safe.”
I am safe.
I am safe. And you are safe, right?
I am safe. I am safe.
I feel great!
All right. So that’s an example of a technique that can get you out of fight or flight. If you had a hand temperature thermometer, you’d notice that your hands warmed a little bit.
I feel it.
Okay. So a hand thermometer like that, a very sensitive one, is an example of a device that can help people get out of chronic pain because as people learn to do that, get themselves out of fight or flight very quickly… The problem of being in fight or flight if you have chronic pain is it makes things worse. Fight or flight is “There’s danger! There’s danger! There’s danger!” What’s pain? Pain is “There’s danger! There’s danger! There’s danger!” They work together like this. If you're in a fearful kind of mode, you have more pain, basically. Your brain figures there’s danger and creates more sense of pain.
But I’m curious because pain is not-- Like the lion, right? Pain is not something that you can fight or fly away from.
Right. Right. Pain is not like the lion. What’s like the lion is the news report about the latest number of COVID cases in your community or your boss saying that he needs a report by 2:00 today and you were planning to go to the dentist.
You know, all the kind of little stresses of everyday life—those are the lions of today.
Is that where we say that stress can cause inflammation?
And I’m curious there. I mean the next obvious avenue of inquiry is that there’s a connection between inflammation and cancer.
Yeah, and there you get beyond my expertise.
Mm-hmm [yes], mm-hmm [yes].
So at first I was thinking, well, thermometers, but then that’s not really that great a contribution. I mean you can buy thermometers—you know, not quite as good as the ones that I made for this purpose, but almost as good. It’s not clear you really have a product here, you know, selling thermometers. So I was wondering if there could be a better biofeedback device for pain, and I think that the best biofeedback device for pain would be something that would measure your pain, and to many digits. Like you normally say pain 0 to 10 scale. “Well, I think it’s a 7. Well, it could be a 6,” you know? “Well, I don't know. Maybe it’s a 7,” you know? But it’s pretty imprecise. I don't know if you’ve been in pain and have been asked to give yourself a score on the 0 to 10 scale.
And you know how it’s kind of like, well, within one digit it’s pretty hard to say.
Right, and then there are always the sociological factors like how much of a nuisance to the nurses do you want to be really?
Yeah, exactly. So there are a lot of factors that go into it, and it’s hard to be precise. But let’s say you had a pain meter that read out that your pain was 5.32.
Well, on a 0 to 10 scale.
Oh, I see. Okay. Right.
So now you put your hand on your heart, right, and then you say, “I am safe. I am safe. I am safe,” and you see it goes down to 5.30 from 5.32.
But what’s being measured beyond this subjective communication of you self-assessing and communicating that? I mean as opposed to like the number of lipids in your blood or something like that that has nothing to do with you having feelings about yourself and communicating those feelings.
At the moment what we’re doing is we’re measuring pulse, and we’re measuring galvanic skin response, and we’re measuring subtle motion. The instrument makes about 20 different measurements simultaneously, real-time, for 10 minutes, and we have people self-identify what their pain score is. These are chronic pain people, so “Today my pain is a 7,” and then they do a 10-minute recording with all these sensors.
So then right now we have 50 or 60 of these recordings. We’re using deep learning as well as other machine learning techniques including feature recognition to see if we can predict a person’s chronic pain from those physiological signals. The idea is to make a meter based on physiological signals that is a pain meter that is in rough correspondence with your perceived…your self-assessed pain. But the beauty of it is that it’s objective and that it’s fine. [Chuckles] You know, it’s like you could make it…because it’s just taking the readings of all these sensors and it’s combining them in some way and it can make as many digits as you like, right?
So it could make 5.32, and the beauty of that is you can see what you're doing. Otherwise, you know, you're thinking, “Oh man, I have a pain 6,” and so now you think, “Well, I’ll do something. I am safe. I am safe. I am safe.” Now you say, “What is my pain?” Well, gee. You can't see a tiny difference, right? I mean, I don't know if it’s better or worse. But if you have a meter that’s gone down—it’s 6.32; now it’s 6.3—your brain says, “Oh, okay. I’m going in the right direction.” You know, just like the brain learns to warm your hands, you don't really know how it works. You try various practices, but your brain figures out how to warm your hands. I mean, you're not saying, “Open this vessel. Open this vessel. Decrease the tension here and put this hormone there. Do this, this.” Your brain is figuring out how to raise the temperature of your hands, and your brain can figure out how to lower your pain if it has a good enough feedback.
What does the instrumentation look like? How does a patient interface with these devices that you're building?
For the present incarnation, you have a neck pillow like that you use for airplanes. You have a headband, a cloth headband, and you have a wristband, and there are sensors on your fingertips that are held on with Velcro. That’s the present incarnation, but I’m thinking that it will become much simpler as we learn what sensors are the most important. You know, we put in a lot of sensors because it’s hard to get people to volunteer and so on. It’s hard to do all these measurements out in the field, and so the idea was let’s put in an abundance of sensors and then figure out which ones are actually needed, or which ones are the most useful.
I’m curious, Paul. Maybe in recent years there have been advances in Western medicine for appreciating the connections between the mind and the body that you're talking about, but I’m curious if you’ve ever explored… I’m thinking of Eastern medical traditions for which these connections have been much more apparent and for hundreds, if not thousands, of years.
Sure. I mean I’ve just been looking at Chinese pulse diagnosis, for example. I mean, there’s a lot of work done on pulse diagnosis, and it’s ironic that we’re discovering with a chronic pain meter that the pulse is the best diagnostic, and very subtle details of the pulse like how the slope of the rise of the pressure compared to the slope of the decrease of the pressure in an individual heartbeat. So there are parameters of the individual heartbeat that turn out to be highly related to pain, and they would be the kind of thing that a well-trained doctor might be able to feel with his hands. I mean the Chinese, they’re going to put three fingers on your wrist like this and then they’re going to do it different pressures. So I’ve got a new respect for the possibility that there is some real science behind that, that these doctors are picking up subtle features of the pulse that are related to health.
Then the greater connection, though, is all the kind of Eastern focus on mind-body health and the realization that if you feed your mind with COVID disaster stories all day long, you're not going to be a healthy person. You're going to really get yourself into serious trouble. The kind of mental hygiene that you learn from the Eastern religions and the idea that you have to take care of your mind is really useful for recovering from chronic pain as well as many other problems, for example chronic anxiety. You know, you have to be a little bit gentle on yourself: self-compassion. It can help to meditate. You need to do things to help your mind be more useful to you and the people around you, so you're not just a victim of your mind. You're not your thoughts. You're not your thoughts. You're not your thoughts, and in fact, you can change your thoughts, and you can change your thoughts in ways that make you happier and healthier and the people around you in the same way. So it’s really kind of a continuation of that, the notion that you can use the power of your own mind to cure the problem of chronic pain.
And you know, I can't help but think—and I’m sure you’ve explored this as well—that if this becomes more widely adopted, it could be a real effective solution to the opioid crisis, right, which is fundamentally an attempt to put an easy fix to the issue of chronic pain, right?
Absolutely. In fact, I read the most interesting article this morning in Scientific American about ending the opioid crisis. It was fascinating to me because I came upon all this stuff about the cognitive techniques and Qigong and things like this for overcoming chronic pain. I discovered that all on the Internet. But as I talked to a physician, and now this article was pointing out, this was the gold standard treatment for chronic pain up till the late 1990s. People knew this! There were programs at UCLA to recover from chronic pain using exactly this kind of thing—using the cognitive techniques and all this kind of stuff and biofeedback, all this kind of stuff. This was the mainstream gold standard treatment for chronic pain. Opioids at that time were used for acute pain, for which they’re very useful, and other things for which they are also useful. But the idea came about that OxyContin, in particular, was not very addictive and so wow! You don't have to do all this work retraining your brain and all this kind of stuff and having all these very expensive programs, in-resident programs where the person spends weeks in residence learning these techniques. You don't need all that. Just take OxyContin, right?
It’s cheaper! So all of a sudden opioid use quadrupled over a period of 1999-2010 and continued to grow because of the idea of you don't have to do all this retrain your brain stuff. Just take opioids.
But now that’s blown up in our face, and so we’re going to go back to the future. We’re going to go back to what people knew 20 years ago: that you can overcome chronic pain by using your own mind and doing gentle exercises and all the kind of thing…an interdisciplinary socio-bio program that people knew 20 years ago! Hopefully they’ll do it even better this time around with knowledge of what works best. I’m seeing new places that are bringing up new initiatives and new ways to cure chronic pain that are basically retrain the brain revisited.
I’m so grateful to Chancellor Yang, who I work with. When I started running that workshop—and I sent him the results of the workshop because I had used some of his students as assistants, and basically he let me know, “You shouldn't be doing this work. You shouldn't be running workshops to help people recover from chronic pain.” He denies he told me this, but this is what I got out of it: he pointed out that my core strength is building gadgets. He said that’s something you can do that other people can't do. This running workshop to help people recover from chronic pain, other people can do that—not anyone, but lots of people can do that.
So better for me to build gadgets like the pain meter, which I’m hoping can be a really effective biofeedback device. See, the thing is people love gadgets, and something that can be cured by a gadget is real. So I would love to have something on Amazon that would sell for $150, you know. Cure your chronic pain using this gadget. They would get the gadget and it would have to be coupled with some kind of motivational program with “Congratulations on your sessions today. Your recovery progress score is now 108!”, “It will really help you if you watch this short video in addition to your biofeedback sessions for tomorrow” and that kind of thing. It would have to be used in some kind of a program, but my dream would be that adding an effective biofeedback device could really help any program for chronic pain recovery. That’s my dream.
And in terms of… You mentioned before that the instrumentation will be improved and refined as we get a better understanding of the feedback mechanisms in the body that are actually the source of pain, right? So what’s the quantum leap there that happens that will allow you to refine your instrumentation so that you don't need the neck pillow and the headband and the wristband and every other sensor on the body, which sounds to me like you need all of these things to take a wide sweep of everything that’s going on, but in fact it’s actually going to be much more localized. What’s the advancement in knowledge that’s going to allow that instrumentation to be smaller and more refined?
Well, it’s coming out of the deep learning analysis and the sophisticated analysis that’s being used to go from the sensor data to the predicted pain score and basically… I was just looking at a graph this morning from my computer science collaborator where he’s rating the various sensors that we have in terms of how valuable their contribution was, and clearly we’ll eliminate the less valuable ones from future instruments.
So in terms of deep learning, you would say that your research is a benefactor of all of these amazing advances that are happening in computational power.
Absolutely. Absolutely. And also just even the pulse analysis of being able to analyze all of the pulse shapes in a long data record. You know, 10 minutes, that’s a lot of pulse shapes, and to be able to automatedly analyze all of that and leave out sections where there have been disruptions due to motion… Yeah, absolutely. This kind of machine learning is going to be absolutely essential, and I’m very fortunate to have a wonderful collaborator named Linda Petzold who was Research Professor of the Year at UCSB a while back. She’s a really, really good computer science professor, and so it’s wonderful to be able to collaborate with her and her wonderful students Destinee Cheng and Yun Zhao. Also, I’m collaborating with Chancellor Yang, who is a mechanical engineer, and I have his student, Franklin Ly, working with me. Franklin, together with Elyes Turki, a physics student, have done a wonderful job on the computer data acquisition and data display and user interface. And I’m collaborating with a psychologist, Michael Miller. And I’m collaborating with a neuroscientist, Ken Kosik. That’s a separate collaboration, the neuroscience collaboration that I’m doing now, but it’s interrelated, the whole idea of understanding how these pain circuits work and understanding how neural circuits work and understanding that neural circuits can run with an impetus of their own. If you reflect on your own experience, you find that you don't need any input for your brain to be active, right? Your brain can amuse itself with no sensory input, right? Think of tunes running through your head or thoughts about the past or future.
It can just keep on going in sometimes repetitive patterns that are boring as hell if you actually pay attention to them because they’re so repetitive. But you can have these things running in your brain with no input. So just understanding the way the brain works and the way that you get these neural circuits and the way these neural circuits will tend to self-activate and just keep running. That kind of knowledge is very useful as a fundamental foundation for why you have to break those patterns, figure out a way to break those patterns to recover from chronic pain—or if your brain is doing something you really don't want it to be doing, that it’s worth investigating whether you can take control over those undesirable mental processes.
Now the other issue that I wanted to touch on was your collaboration with Ken Kosik. It sounds like you first got to work with him as a result of him joining this larger collaboration on chronic pain, but then from there--
Oh, that’s not it.
No. Actually, it started quite separately from that.
Oh, I see.
It started because he’s an expert on Alzheimer's disease. I was at Chancellor Yang’s house for dinner one night, and it was one of these dinners that’s very pleasant where he’s got some people that he wants to impress like the head of the National Science Foundation or something like that was the most recent one. I forget which one where he had Ken Kosik, but I think it was some a trustee or two that he had. So he invites some faculty members kind of to sit around with them and tell about their research with the idea that look at all this wonderful research that’s going on at UCSB.
Well, Ken and I were both at one of these dinners and I talked about bone and Ken talked about Alzheimer's disease. I was impressed with Ken and I thought, Alzheimer's disease. Wow, that’s an interesting challenge. So Ken and I got together. We wondered whether there would be a possibility of collaborating because we were both kind of interested in that possibility, and it turned out that Ken really wanted to get into studying neurons grown on multi-electrode arrays because he was convinced that the whole brain kind of studies that are going on for the Alzheimer's and so on, that they’re wonderful, but that there’s an unmet need for trying to understand what goes on with Alzheimer's disease and other neurodegenerative diseases at the more neural circuit level, you know, of individual neurons interacting with each other. How does that get screwed up? What happens there just at the most kind of basic levels—not talking about the whole brain and plaques and all that kind of stuff, but what goes on at the really basic level? So I joined with him in the effort to try to figure that out and worked on inventing a neural circuit probe to try to probe those circuits and that kind of thing. So that work is continuing in terms of trying to understand how the brain works on a very microscopic scale.
Mm-hmm [yes], mm-hmm [yes]. Well, Paul, now that we’ve sort of gone right up to present day in terms of the narrative, I think for the last portion of our talk I want to ask you first a few broadly retrospective questions about your career, and then talk about some things looking forward. So the first one is we haven't really talked much about, as a professor, your work both as a teacher and as a mentor. So my first question is in terms of teaching, given all of your interdisciplinary interests, right, what kinds of courses do you teach undergraduates? I mean, are you teaching like a physics 101 or are you leaving that kind of a bread and butter course to your colleagues? What courses are you teaching undergraduates and at what level?
Okay. Well, I’ve retired from teaching, but when I did teach, probably the course that I taught the most was physics for biological sciences, the big courses for the biology students. I taught that course many times -- physics for premeds. And I taught condensed matter physics sometimes, and I spent a lot of time revising the undergraduate labs. I taught the electronics lab. I taught quantum mechanics once. Yeah, so that’s the variety of courses that I taught.
What were your favorite concepts to convey to students, particularly those who were taking this course not because they were pursuing physics, [but] because they were pursuing something else?
Well, with the biologists, for that course I wanted to get across the concept that mathematically modeling phenomena is useful in many contexts, including medicine, and that the reason physics is still part of your curricula as a biology student is to teach you mathematically modeling things with the simplest systems. I mean in biology you have these enormously complicated systems like a fruit fly, for God’s sakes. I mean so many things are going on at once, but what do we study in physics? We study a ball that you drop, and we’ll neglect air resistance. We’ll just drop a ball and see how long it takes to fall. So that’s a very, very, very, very simple system compared to anything that you get involved in in biology. So if you want to learn how to mathematically model physical phenomena, physics is good because you model really simple things like, you know, a ball rolling around along a frictionless track or things like this, or a projectile shot in the air and comes down and you neglect air resistance. So you basically can learn the skill of mathematically modeling physical phenomena using the simplest possible systems.
Now on the graduate and post-graduate level, right, we’ve talked about how mostly it seems like you're a benefactor of not really having a strong advisee record, both as an undergraduate and in graduate school. And yet for your career, you’ve had your lab. You’ve had numerous graduate students. You’ve had numerous post-docs. So I wonder if you can comment on your style as a mentor at the graduate level: the way that when you decide to be hands-on and when you decide to be hands-off, the kinds of career advice that you give up and coming young scholars and things like that. What is your style as a graduate mentor?
My style is to first present interesting alternatives to students, the different possibilities to try to inspire them with the idea that their research should help somebody eventually, you know, that I’m interested in helping people. I’m not interested, in my lab, in just purely intellectual endeavors. I want at least to have the hope that in the future this could lead to helping someone. Beyond that, I like to present them alternatives and then let them choose. I hope that they do their own thing productively and that I can say, “Wow!” and be very happy when they make accomplishments. As they progress I encourage them to follow up ideas that they come up with. I try to catch students doing good work and praise them for it. That’s my basic style.
Now I love asking this question, but with you I’m particularly intrigued, given all the twists and turns of your research career. That is, sort of going back to your classical education at Berkeley in physics, what are some of the concepts or fundamental laws in physics that stay with you, that are close to you, that are relevant to you on a day-to-day basis, that either inform the way you go about building something or the way you go about formulating a research problem or the way you go about coming up with a solution to that problem?
[Pauses] I don't know. I would say-- One thing would be that no matter what you're going to do, it’s going to end up being time-consuming and complicated, so you may as well pick something where at least there’s the potential for helping someone in the end, you know, because you can otherwise just get lost in the intricacies of a problem. And every level you get to, there’s always another level.
This company I remember reading about, they were saying they started this research endeavor to answer a few questions, and now a year later, as the questions got answered, new questions came up and in some ways they’re as confused as ever. But they feel they’re confused at a higher level about more important things.
So the idea that research in any kind of thing can just take a life of its own, and you can consume enormous amount of resources and time doing something. So you may as well do something worth doing and give some consideration to whether it has the potential to help people. And this is my own point of view. A lot of people feel 180 degrees opposite of that. A lot of people feel like knowledge for its own sake is the highest, and things that are done for a material gain in the world and better widgets, this is to be disdained because what’s really important is the intellectual life and understanding quark-gluon interactions and understanding nature at its most fundamental limits. Building gadgets and doing practical things—that’s sort of beneath us. I respect those people. I mean I’m glad there’s that sort of people around, but I’m not one of them.
Mm-hmm [yes]. So Paul, I think for my last question, the looking ahead question, given how much you have thought about this issue of making that difference and involving yourself in applying the things that you understand to actually contributing materially to improving the way people live, right? So because it seems like there’s a theme with all of your contributions that if the standard is you want that picture of the person who’s really been helped by x, right? So my question is what are you most optimistic about in terms of the research that you’ve done, in terms of the gadgets that you have built, that that metaphor of that person that you can look at on your desk—what are you most optimistic about in terms of achieving that satisfaction in your own lifetime, in other words of seeing that yourself? And projecting ahead 50 years, 100 years, something like that, what might be the long-term arc of your research that you might not personally live to see, but you can appreciate how in the future you will have contributed to something that is not so obvious now and will really be an enormously important material benefit to humanity?
[Pauses] Well, I think that if the Osteoprobe does get FDA approved, and if people do the kind of experiments you were mentioning (diet, exercise, so on), it could prevent hundreds of thousands of fractures, and each fracture… I mean, when I was in Barcelona and you go to room after room of all these poor elderly people who had a hip fracture—they’re laying on their back. They have their legs up. They can't roll over. Their legs are up in a traction kind of device thing and they can't even roll over, you know. They’re just laying there on their back and their life is never going to be the same.
So being able to ease that burden on the quality of life is important to me. I’m very interested in quality of life, not so much length, even. I mean a lot of people are focused on things that kill you like heart disease and cancer. I’m more interested in things that affect the quality of life like bone fracture and chronic pain. What are the things that don't kill you but make you miserable? Well, bone fracture can, but it doesn't kill most people. But it really debilitates everybody’s quality of life. They’re in a walker. They lose the ability to do things. Same way with chronic pain. They lose ability to do things. They don't play with their friends anymore. They don't go swimming anymore. You know, they’re in chronic pain. They lay in bed.
So the research legacy that I would like would be to help improve people’s quality of life, and in particular, in the case of the chronic pain, helping people realize that they can change what goes on inside their head for their own benefit and that this is not just woo-woo, new-age thinking, but that it can be measured with an instrument. You can see it on an instrument. You can see the results of working on your head in a physical instrument, and that gives it a kind of a reality and helps create a growing sense that you can improve your quality of your own life and that you can do it by retraining your brain with the aid of gadgets.
Well, Paul, it’s been an absolute pleasure speaking with you today. I really want to thank you for your time.
Good! Thank you!